Film for medical use, consisting of linear block polymers of polyurethane and a method for the production of such a film

ABSTRACT

Porous films for medical use are provided comprising linear block polymers of polyurethane and urea containing hydrolyzable ester groups which are spaced along the carbon chain backbone of the film predetermined distances, so that upon hydrolysis of the ester groups fragments of the polymer are formed which have a size which can be secreted from the body of a mammal, the porous film including pores having an average pore size of up to 600 μm.

FIELD OF THE INVENTION

The present invention relates to a film for medical use, which filmconsists of linear block polymers of polyurethane and urea containinggroups which can behydrolyzed. More particularly, the present inventionrelates to a porous film, and is designed to be used as a temporaryimplant after operations on, or damage to, a human body or a mammal.More particularly, the present invention relates to a procedure forobtaining the desired porosity.

BACKGROUND OF THE INVENTION

The healing of living tissue after an operation or damage incorporatescomplicated processes which are set in motion, involving a range ofdifferent cell types. In rough outline, the following processes takeplace in the following order: first a matrix of fibrin is formed, thenthe epicells begin to divide and bridge over the injury. Under theepithelial layer fibroblasts are already beginning to build connectivetissue consisting of collagen and base substances. The connective tissueis gradually vascularized and condensed into scar tissue.

In other cases, for example in the healing of broken bones, theformation of the matrix is followed by the growth of stem cells, whichare categorized as chondroblasts. These form soft callus, consisting ofcartilage, in the fracture. Fibroblasts migrate into the cartilage andform zones of collagen. Then osteoblasts enter and form new spongy bone.The final phase in the healing process consists of the conversion tohard bone and restoration of the remaining structure. This can takeyears before it is completed.

Even if the healing process goes generally well, its complicated coursecreates many possibilities for going wrong. For example, micro-organismscan affect it or a wounded area can act together with wrong “neighboringareas” and form a joint growth. Often there are fibroblasts which growquickly and are a source of unwanted connective tissue formation. Thiscan prevent reconstruction of bone tissue or other desired tissue.

Therefore, there has long been a wish to be able to assist theself-healing process and overcome the problems set forth above.

SUMMARY OF THE INVENTION

This and other objects have now been realized by the invention of aporous film for medical use comprising a linear block polymer ofpolyurethane and urea containing hydrolyzable ester groups and having acarbon chain backbone, the hydrolyzable ester groups being spaced alongthe carbon chain backbone a predetermined distance such that uponhydrolysis of the ester groups fragments of the polymer are formedhaving a size which can be secreted from the body of a mammal, theporous film including pores having an average pore size of up to 600 μm.In a preferred embodiment, the porous film has a predeterminedthickness, and the porosity of the film varies across the thickness.Preferably, the porosity of the film is asymmetric across the thicknessof the film.

In accordance with one embodiment of the porous film of the presentinvention, a mesh of biodegradable material is laminated to the porousfilm.

In accordance with another embodiment of the porous film of the presentinvention, the film forms a coating on individual threads of abiodegradable fabric.

In accordance with the present invention, a method has also been devisedfor the preparation of a porous film for medical use comprisingpreparing a solution of a linear block polymer of polyurethane and ureacontaining hydrolyzable ester groups at a concentration of between 5%and 30% in a solvent, applying a thin layer of the solution onto asurface, and treating the coated surface by evaporating the solvent ortreating the layer with a polymer precipitating agent. In a preferredembodiment, the concentration of the polymer in the solvent is between10% and 20%.

In accordance with one embodiment of the method of the presentinvention, the polymer precipitating agent is water, methanol oracetone.

In accordance with another embodiment of the method of the presentinvention, the method includes controlling the size of pores of theporous film. In a preferred embodiment, controlling of the size of thepores comprises adjusting the polymer concentration, selecting thesolvent having a predetermined volatility, selecting the temperatureduring the process, or selecting the time of the process of evaporatingand treating.

In accordance with one embodiment of the method of the presentinvention, the solvent comprises a mixture of a plurality of solvents.In a preferred embodiment, the method includes controlling the size ofthe pores by selecting the plurality of solvents having a correspondingplurality of volatilities.

In accordance with another embodiment of the method of the presentinvention, the method includes adjusting the pore size of the pores byconditioning the porous film during the carrying out of the method. In apreferred embodiment, the conditioning comprises immersion of the porousfilm in at least one solvent or thermal treatment of the porous film.Preferably, the method includes immersion of the porous film in amixture of solvents and anti-solvents.

According to the present invention, a porous film has been providedwhich can be used for medical purposes consisting of linear blockpolymers of polyurethane and urea containing hydrolyzable ester groupsat such a spacing in the carbon chain that on hydrolysis of the estergroups such small fragments are formed that they can be secreted from ahuman body, or that of a mammal, which film is characterised in that itis porous with an average pore size up to 600 μm.

According to the present invention, the film is further characterized inthat the porosity can be varied across the thickness of the film.

According to the present invention, the porosity through the thicknessof the film can be asymmetric, i.e. a thin outer layer has lowerporosity.

According to the present invention, it is often appropriate that thefilm is laminated with a mesh of biodegradable material.

According to the present invention, the film can be made up of a coatingon the individual threads in a biodegradable mesh or the like.

The present invention also includes a method for the production of aporous film for medical use consisting of linear block polymers ofpolyurethane containing hydrolyzable ester groups, in which procedure asolution of the polymers with a concentration of 5 to 30% is applied ina thin layer on a surface, after which the solvent is evaporated and/orthe layer is treated with a polymer-precipitating agent.

According to the present invention, the precipitating agent can be bestchosen from the group consisting of water, methanol and acetone.

According to the present invention, the porosity is adjusted by means ofthe polymer concentration, where high concentrations give small pores,by means of the solvent, where highly volatile solvents give smallpores, by means of temperature, where high temperatures give small poresand/or time, where short evaporation or precipitation times, asappropriate, give small pores.

According to the present invention, a mixture of two or more solventswith different volatilities can be used to effect variable porositythrough the film thickness.

According to the present invention, the porosity of the film can also beadjusted by the conditioning of an already-formed film by immersing itin a solvent or a mixture of solvents and non-solvents and/or by heattreatment.

Porous films can assist in preventing undesired growth of cells byacting as a barrier over a wound area. In addition, porous films can beused to repair or replenish a periosteum in the case of transplants ofe.g. cartilage. The porosity allows transport of dissolved substances,such as metabolites and/or proteins through the film. If the pore sizeis sufficient certain cell types can also grow in the film. Films withvery large pores can also permit vascularization. For these variousprocesses the following limiting values for the average pore sizes canbe given:

<1 μm diffusion of dissolved components and growth of collagen,

<5 μm no growth of fibrous tissue,

<15 μm relatively little growth of fibrous tissue,

40-200 μm growth of fibrous tissue plus vascularization,

>600 μm reduced growth of cells and necrosis of tissue.

The polymer used in the present films is degradable into harmlesssubstances which are eliminated from the body by secretion ormetabolizing. According to the present invention, the time fordegradation is not too short so that one is able to avoid locally highconcentrations of degradation products. The speed of degradation is alsovaried in order to suit the need in various applications.

The requirements for the mechanical properties of the films hereof canvary depending on the application. In many applications the tearstrength is especially important, e.g. when the films are to be fixedwith pins or the like or sewn firmly. In cases which are very demanding,the modulus of elasticity, tear strength, etc. can be improved bylaminating the film to a mesh of biodegradable fibers. Alternatively,the mesh can be impregnated or coated with a solution or dispersion ofthe polymer with subsequent removal of the solvent.

DETAILED DESCRIPTION

It has become evident that porous films and sheets with the desiredproperties can be produced from polymers of the type linear blockpolymers of polyurethane urea. Suitable polymers are produced by the useof diisocyanates, diols and carbon chain lengtheners according tomethods known for the specific components. In order to form films themolecular weight of the polymers should be >10,000 Daltons,preferably >100,000 Daltons.

A convenient technique to produce the polymers is to use the so-calledpre-polymerization technique, i.e. first produce anisocyanate-terminated pre-polymer and thereafter lengthen its carbonchain with a diamine so that the desired molecular weight is obtained.The equations for the reaction can be written as:

2 OCN—R₁—NCO+HO—R₂—OH→OCN—R₁—NHCO—O—R₂—O—CONH—R₁—NCO  (1)

OCN—R₁—NHCO—O—R₂—O—CO—NH—R₁—NCO+NH₂—R₃—NH₂ - - - - --—[—CONH—R₁—NHCO—O—R₂—O—CONH—R₁—NHCONH—R₃—NH—]_(n)—  (2)

where at least one of R₁, R₂ and R₃ must contain one or more estergroups in the carbon chain in order to meet the requirement fordegradability into small fragments. It is also possible to use mixturesof several pre-polymers in order to achieve special effects, e.g. tointroduce groups which can react after polymerization to introducephysiologically active groups into the polymers. In addition, smallquantities of carbon chain terminators can be added to limit the uppermolecular weight.

The diisocyanates which can be used arediphenylmethane-4,4′-diisocyanate (MDI),dicyclohexylmethane-4,4′-diisocyanate, cyclohexyl-1,4-diisocyanate,toluylene diisocyanate and many more commercially availablediisocyanates and laboratory-produced species, e.g. those based on aminoacids, such as 1-lysine methyl ester diisocyanate.

The diolefines used can be simple aliphatics, such as ethylene glycol,diethylene glycol or higher oligomers, tetramethylene oxide glycol orhigher oligomers, diol esters such as oligocaprolactone diol,oligoethylene glycol adipate diol, oligodiethylene glycol adipate,dimethylol propionic acid, dimethylol propionic acid methyl ester,trimethylol propane monoallyl ether and many more.

Carbon chain extenders can be simple diamines, such as ethylene diamine,1,3-propylene diamine or 1,2-propylene diamine. They can also containester groups in the carbon chain in order to permit degradation byhydrolysis. It is possible and often expedient to use mixtures of carbonchain extenders.

Primary or secondary monoamines can be used as carbon chain terminators,e.g. diethylamine, morpholine or propylamine. Here also, mixtures can beexpedient.

Reaction (1) in the reaction scheme set forth above can be carried outin bulk at elevated temperatures e.g. 70 to 80° C. for MDI or 100 to110° C. for dicyclohexylmethane diisocyanate. In the presence of acatalyst the reactions can be carried out at significantly lowertemperatures. However, reaction (2), the carbon chain lengthening, isperformed in solution on account of the high speed of reaction and thegelling tendency of the polymer formed. The resulting polymer solutioncan be used directly or after dilution for the production of a film orsheet. In certain solvents, e.g. acetone, the polymer so formed isprecipitated and can be filtered off and then re-dissolved in a solventfor the same, e.g. dimethyl formamide, dimethyl sulphoxide or dimethylacetamide.

The films of the present invention are formed from solutions which areapplied as thin layers on a planar surface, after which the solvent isevaporated and/or the film is treated with a precipitating agent. Toobtain a porous film the polymer concentration must be from 5 to 30%,preferably 10 to 20%. After application the solvent can be wholly orpartially evaporated or removed by addition of an antisolvent. Examplesof such anti-solvents are water, methanol and acetone.

A prerequisite for porosity is that the polymer solution at some stageof removal of the solvent forms a gel, i.e. coagulates. Polymersaccording to the present invention have a pronounced tendency forcoagulation by the strong interaction of the blocks by means of phaseseparation and hydrogen bonding. Important other factors, which favorgel formation, are high polymer concentration and high molecular weight.

Pore size and pore size distribution can be adjusted with concentrationand the precipitation conditions associated with addition of theanti-solvent. Alternatively, a pre-produced film can be conditioned withsolvent, mixtures of solvents and anti-solvents and/or thermaltreatment. Conditioning is carried out by dipping a pre-produced filminto a solvent which is later allowed to evaporate or by warming,whereby the film swells up. In this manner, the pore sizes and theirdistribution are adjusted to the desired values.

The films according to the present invention can be produced frompolymer solutions in several ways. The simplest way is by means ofpiece-by-piece production on a surface, e.g. a glass plate, onto which alayer of polymer solution of controlled thickness is spread with anapplicator, after which the solvent is removed by evaporation orprecipitation under carefully controlled conditions. Continuousproduction can be carried out by applying the polymer solution to amoving band which carries the material to a zone for precipitation andthereafter to one or more zones for post treatment and final removal ofthe film from the band, which is then returned.

The film strength can be increased by stretching. This causesorientation of the polymer molecules and alteration of the sizes andform of the pores. As a result, the strength increases in the directionof stretching. With biaxial stretching the strength in two dimensionscan be increased.

An alternative way of increasing the strength of the films of thepresent invention is to combine them with a mesh of degradable fibersof, for example, polyurethane and urea according to the description inSwedish Patent No. 505,703. This patent discloses that the mesh can bepartly laminated with a previously prepared film or impregnated or themesh strengthened with polymer solution followed by evaporation ofsolvent and/or precipitation according to the methods described above.

A method of producing a porous film on curved surfaces is by dipping.For this a film former, such as a pipe sealed at one end, is dipped intoa polymer solution. The film former is taken out, and the polymer isconverted to the solid form by evaporation of solvent and/or coagulationwith an anti-solvent. The procedure can be repeated until the desiredfilm thickness is obtained, after which the film is slid off the former.

The present invention may also be more fully appreciated with referenceto the following examples.

EXAMPLE 1

A pre-polymer was produced by reacting diphenylmethane diisocyanate(MDI) with polycaprolactone diol (molecular weight 530) in the molarratio of 2:1 at 70 to 80° C. for 2 hours. 32.35 g of the resultingpre-polymer were dissolved in 138 g of dimethyl formamide (DMF) and thechain extended with 2.35 g of 1,3 diaminopropane and 0.08 g of dibutylamine in 59 g of DMF at 0° C. The solution was diluted with 12.5% and 1%LiCl was added to reduce the viscosity.

Part of the resulting polymer solution was spread out on a glass plateto a thickness of 300 μm with the help of an applicator. Part of thesolvent was evaporated in a fume cupboard at 20° C. over 20 minutes. Thefilm whitened thereby, signifying phase separation. The remainder of thesolvent was then removed by washing with water. The film so formed wasexamined using a scanning electron microscope (SEM) and exhibitedthroughpores with an average diameter of 2 μm.

EXAMPLE 2

Part of the polymer solution of example 1 was applied to a glass plateand the solvent evaporated in a fume cupboard at 20° C. for 14 hours.The residual DMF was washed away with water. The film so formed had athroughpore structure with pore sizes between 2 and 7 μm.

EXAMPLE 3

Part of the polymer solution of example 1 was applied to a glass plateand immersed in acetone for 10 minutes, whereby the polymer separatedout. The acetone and residual DMF were washed away with water. The filmso formed had a throughpore structure with pore sizes around 1 μm.

EXAMPLE 4

Part of the polymer solution of example 1 was applied to a glass plate.Part of the solvent was evaporated by warming the glass plate in twominutes up to 100° C. The remaining solvent was evaporated in a fumecupboard in one hour at 20° C. The film so formed was washed with waterto take away the remaining DMF. The film so formed had a throughporestructure with pore sizes between 2 and 7 μm.

EXAMPLE 5

12.3 g of the pre-polymer obtained in example 1 were dissolved in 52.5 gof dimethyl formamide (DMF) and had the chain extended with 0.9 g of1,3-diaminopropane and 0.06 g of dibutylamine in 22.5 g of DMF at 20° C.

Part of the resulting polymer solution was applied to a glass plate to athickness of 500 μm with the help of an applicator. The solvent wasevaporated in a fume cupboard for 14 hours at 20° C. The residual DMFwas washed away with water.

EXAMPLE 6

A pre-polymer was produced by reacting dicyclohexane methanediisocyanate (H₁₂MDI) with polycaprolactone diol (molecular weight 530)in the molar ratio 2:1 at 100-110° C. for four hours. Additionally, apre-polymer was produced by reacting H₁₂MDI with dimethylolpropionicacid in the ratio 2:1 in dimethyl sulphoxide (DMSO) at 75 to 80° C. forone hour. 26 g of pre-polymer 1 and 8.7 g of pre-polymer 2+DMSO weredissolved in 66 g of DMSO and the chain extended with 2.12 g of1,3-diaminopropane in 20 g of DMSO at 20° C.

Part of the resulting polymer solution was applied to a glass plate to athickness of 300 μm with the help of an applicator. The solvent wasevaporated in a fume cupboard for 14 hours at 20° C. The residual DMFwas washed away with water.

EXAMPLE 7

A pre-polymer was produced by reacting diphenylmethane diisocyanate(MDI) with polydiethyleneglycol adipate (molecular weight 550) in themolar ratio 2:1 at 70 to 80° C. for two hours. 13.2 g of the resultingpre-polymer were dissolved in 34 g of dimethylformamide (DMF) and thechain extended with 0.68 g of 1,3-diaminopropane and 0.05 g dibutylaminein 22 g of DMF at 20° C.

Part of the resulting polymer solution was applied to a glass plate to athickness of 500 μm with the help of an applicator. The solvent wasevaporated in a fume cupboard for 14 hours at 20° C. The residual DMFwas washed away with water.

EXAMPLE 8

A pre-polymer was produced by reacting diphenylmethane diisocyanate(MDI) with 3-allyloxy-1,2-propane diol in the molar ratio 2:1 at 70 to80° C. for two hours. 6.12 g of the resulting pre-polymer and 17.62 g ofthe pre-polymer prepared in example 7 were dissolved in 65 g of dimethylsulphoxide (DMSO) and the chain extended with 2.17 g of1,2-diaminopropane plus 0.07 g of ethylamine in 3.5 g of acetone and 30g of DMSO at 20° C. The resulting polymer solution was diluted to 15%concentration by addition of 35 g DMSO.

Part of the resulting polymer solution was applied to a glass plate to athickness of 500 μm with the help of an applicator. The solvent wasevaporated in a fume cupboard for 14 hours at 20° C. The residual DMSOwas washed away with water.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

What is claimed is:
 1. A porous film for medical use comprising a linearblock polymer of polyurethane and urea containing hydrolyzable estergroups and having a carbon chain backbone, said hydrolyzable estergroups being spaced along said carbon chain backbone a predetermineddistance such that upon hydrolysis of said ester groups fragments ofsaid polymer are formed having a size which can be secreted from thebody of a mammal, said porous film including pores having an averagepore size of up to 600 μm.
 2. The porous film of claim 1 wherein saidporous film has a predetermined thickness, and wherein said porosity ofsaid film varies across said thickness.
 3. The porous film of claim 2wherein said porosity of said film is asymmetric across said thicknessof said film.
 4. The porous film of claim 1 including a mesh ofbiodegradable material laminated to said porous film.
 5. The porous filmof claim 1 wherein said film forms a coating on individual threads of abiodegradable fabric.
 6. A method for the preparation of a porous filmfor medical use, wherein said porous film including pores having anaverage pore size of up to 600 μm, comprising preparing a solution of alinear block polymer of polyurethane and urea containing hydrolyzableester groups at a concentration of between 5% and 30% in a solvent,applying a thin layer of said solution onto a surface, and treating saidcoated surface by means of a process selected from the group consistingof evaporating said solvent and treating said layer with a polymerprecipitating agent.
 7. The method of claim 6 wherein said concentrationof said polymer in said solvent is between 10% and 20%.
 8. The method ofclaim 6 wherein said polymer precipitating agent is selected from thegroup consisting of water, methanol and acetone.
 9. The method of claim6 including controlling the size of pores of said porous film.
 10. Themethod of claim 9 wherein said controlling of said size of said porescomprises a control method selected from the group consisting ofadjusting said polymer concentration, selecting said solvent having apredetermined volatility, selecting the temperature during said process,and selecting the time of said process selected from the groupconsisting of evaporating and treating.
 11. The method of claim 6wherein said solvent comprises a mixture of a plurality of solvents. 12.The method of claim 11 including controlling the size of said pores byselecting said plurality of solvents having a corresponding plurality ofvolatilities.
 13. The method of claim 6 including adjusting the poresize of said pores by conditioning of said porous film during thecarrying out of said method.
 14. The method of claim 13 wherein saidconditioning comprises a conditioning step selected from the groupconsisting of immersion of said porous film in at least one solvent andthermal treatment of said porous film.
 15. The method of claim 14including immersion of said porous film in a mixture of solvents andanti-solvents.